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Motor Man

Ron Vale has spent a career studying how molecular motors transport cargo within cells. He’s also developed tools to help scientists communicate their findings.

Sep 1, 2017

Anna Azvolinsky

RON VALE
Professor, Department of Cellular and Molecular Pharmacology
University of California, San Francisco
Investigator, Howard Hughes Medical Institute Founder, President, Chairman of the Board, iBiologyYUXIAO WANGIn 1983, Ron Vale was three years into an MD/PhD program at Stanford University, and he already had four publications under his belt. During his first two years, spent in medical school, Vale worked with neuroscientist Eric Shooter. “These were not very influential papers, but they taught me how to start to ask a question, to start and complete the experiments, and how to write a scientific paper,” says the University of California, San Francisco professor. “Having these papers . . . basically gave me a guarantee of a PhD degree, even though I had officially just begun the PhD part of the program,” Vale says. “Now, I really wanted to do something that was bigger, riskier, and exciting.”

Vale became intrigued by microscopy movies generated by his lab neighbors James Spudich and visiting professor Michael Sheetz showing myosin-coated beads moving along the actin cables of purified skeletal muscles. Myosin is an adenosine triphosphate (ATP)–powered motor protein whose motion along actin filaments generates muscle contractions. The two were trying to reconstitute, in vitro, the basic motility that occurs within muscle fibers. Vale, Sheetz, and Spudich wondered whether myosin movement also might account for the dynamic movement of organelles such as mitochondria and transport vesicles along the long giant axon of squid. “I was inspired by the strong visual impression made by Sheetz’s and Spudich’s movies and could imagine a similar mechanism working in axons,” he says.

Vale was studying how nerve growth factor interacts with its receptor at axon terminals and wondered how molecular signals traveled from the axonal terminal to a nerve cell body across a long axonal distance. “There was little known about axon transport. . . . It seemed like an interesting problem to work on.”

“I don’t think that anyone in the field thought that motors would be just floating around
in the cell.”

With Sheetz, Vale discussed ideas to test whether myosin-coated beads would move within axons, using the squid giant axon—which can be as wide as 1 mm, more than 100 times the width of a human axon—as a model. Serendipitous events and many hundreds of hours of laboratory work resulted in Vale, Sheetz, and their collaborators Bruce Schnapp and Tom Reese developing methods to study and visualize transport by molecular motors, including in vitro reconstitution assays, and the discovery of a novel motor protein—which Vale dubbed kinesin—that moves along microtubules by using the energy derived from ATP hydrolysis.

Here Vale discusses how El Niño steered him to Woods Hole and the collaboration that led to the discovery of kinesin; his passion for preprints in biology; and his project to deliver lectures by the best biologists to anyone with Internet access.

VALE VENTURES

Science interests, artistic roots. Vale was born in 1959 in Hollywood, California, where Michael Jackson was one of his elementary school classmates. His mother was an actress and his father wrote screenplays for movies and television.” Neither of my parents had the opportunity to go to college because of World War II and the circumstances of their lives, but what impressed me was how incredibly well-rounded, curious, and self-educated they were,” says Vale. During his childhood, Vale’s mother frequently took him to the Natural History Museum of Los Angeles County, the planetarium, and other science exhibitions, which, he says, sparked his interest in science.

Getting hooked. As a high school sophomore, Vale conducted a circadian rhythms experiment in his parents’ basement using bean plants, designing a device that would measure the plants’ movements. His guidance counselor Ella Hogan, who was also a neighbor, noticed his appetite for science and contacted the University of California to find a professor willing to supervise Vale’s extracurricular research. For the rest of high school, he worked in the plant physiology lab of Karl Hammer at UCLA. The guidance counselor also told Vale about the Westinghouse (now Regeneron) Science Talent Search, a research competition for high school seniors. For his circadian rhythms project, Vale was selected as one of 40 students in the U.S. to attend the semifinalists’ meeting in Washington, DC. “It was eye-opening to meet all of these other kids interested in science and speak to scientists about your work. That’s what really hooked me on science.”

Great role models. In 1976, armed with a full scholarship, Vale entered the University of California, Santa Barbara (UCSB), as a student in the College of Creative Studies, where curricula were designed for independent study. Even before arriving at UCSB, Vale had sought out Beatrice Sweeney, a plant biologist who worked on circadian rhythms, to ask if he could work in her lab. “She was an amazing person, in her 60s and still doing tough circadian rhythm experiments herself, coming in throughout the night to take samples. It was just so obvious how much she loved science. She was quite inspirational to me,” says Vale. In the summer, Vale worked on the epidermal growth factor receptor in C. Fred Fox’s lab at UCLA. “I was this freshman who showed up in his lab and, instead of giving me mundane lab tasks, he gave me my own project and, in retrospect, a remarkable amount of independence,” Vale recalls.

Undergraduate scientist. Back in Santa Barbara for his final year, Vale wrote to Duke University’s Robert Lefkowitz (a 2012 Nobel laureate in chemistry) and worked in his lab over that winter and spring. “It was a big and super-exciting lab that was doing the Nobel Prize–winning work of purifying the β-adrenergic receptor. I learned a lot from seeing this exciting chase for a major goal, and Bob was fantastic and extremely generous. He treated me more like a colleague than an undergraduate,” says Vale. Although his work in the Fox lab resulted in a 1984 first-author paper in which Vale showed that a plasma membrane fraction can inhibit cell proliferation induced by epidermal growth factor, his work in the Lefkowitz lab resulted in the first paper on which Vale was lead author, a 1982 publication on the interactions between insulin and its receptor.

VALE, VALIDATED

Missing squid. Vale entered Stanford University’s MD/PhD program in 1980. In 1983, just as he was beginning the PhD part of the program, he and Sheetz decided to test whether movement of myosin along actin filaments within the squid giant axon was the source of the organelle shuttling that had been recently observed by Robert Allen, Scott Brady, Ray Lasek, and colleagues. Vale and Sheetz planned to use squid supplied by Stanford’s Hopkins Marine Station. But that spring, neither researchers at the station nor commercial fisheries were catching any squid. Only later, it emerged that 1983 was an El Niño year that left the Pacific Ocean along the coast of California too warm for the squid, which had swum off to cooler waters.

“Impetuously, we decided to do the work at the Marine Biology Laboratory (MBL) in Woods Hole, Massachusetts, and within two weeks had set up shop there,” says Vale. When they got there, they were introduced to novel video-based contrast-microscopy imaging techniques being developed by researchers Robert Allen and Shinya Inoue at the MBL, which was “kind of the center of this microscopy revolution at the time,” says Vale. He and Sheetz then teamed up with Bruce Schnapp and Thomas Reese, who had built a video-enhanced contrast electron microscope for their axon experiments. In two Cell papers published two years later, the team showed that organelles could move bidirectionally, not on actin, as Vale had hypothesized, but rather on a single microtubule.

In the summer of 1984, his last before a scheduled return to medical school, Vale challenged himself with reconstituting the microtubule-based axonal transport system, breaking apart the components and trying to put them back together again. He was able to make microtubules from purified tubulin and purify axonal organelles from squid. To Vale’s surprise, when mixed together, the organelles by themselves had no ability to move on the microtubules. Adding back additional soluble proteins from the axon allowed the organelles to move along the tubules. “I thought that the motor would be on the organelles and others thought they would be on the microtubules. I don’t think that anyone in the field thought that motors would be just floating around in the cell.” The discovery that the cytoplasm contained soluble, free-floating motor proteins came about by accident: while doing what he thought was a control experiment, Vale observed that this soluble cell fraction bound to a glass cover slip could move microtubules along the glass surface. He also quickly showed that these soluble motors could attach to beads and cause them to move along microtubules. “That study really told us a lot about how that whole transport system was organized. It also gave us an in vitro microtubule-based motility assay, which the field has been using for 30 years.”

Two-way traffic. In the winter of 1984, Vale took a leave of absence from medical school and stayed on at the MBL, purifying the motor protein and using the new assays to test the protein’s function. “We discovered these assays two weeks before I was supposed to go back to medical school. It was really down to the wire for me to figure out what to do with my future,” says Vale. “Woods Hole is so deserted in the winter, it was like doing science in the 19th century. It was really just you and the science, with no distractions.” During that winter, along with Reese and Sheetz, he identified the previously unknown motor protein, which they dubbed kinesin. Vale credits the name to his mom and her friend, a scholar of classical Greek who told him that kine is Greek for movement. The team further probed the activity of kinesin and found that it moves in one direction, towards the N-terminus of a microtubule, and that another motor protein, later discovered to be a cytoplasmic dynein by Richard Vallee, moves in the opposite direction.

VALE VOICES

Pet projects. In 1986, at the age of 27, Vale set up his own laboratory at the University of California, San Francisco, giving up the idea of finishing his MD degree. For his first 10 years as a professor, Vale continued to perform experiments, and published eight first-author papers. “I wanted to be at the lab bench with everyone else. It was important to be part of the chase, because that’s what motivated me personally.” In 1991, Vale even published a sole-author paper in Cell, when he discovered the first microtubule-severing factor while trying to do organelle transport assays using Xenopus extracts. Then in 1996, while on sabbatical in the lab of Toshio Yanagida, who had developed single-molecule microscopy, Vale developed the first single-molecule fluorescence motility assay for a motor protein.

Shifting gears. After figuring out much about how kinesin works, including working out the protein’s crystal structure in 1996, Vale’s lab shifted focus to dynein—a motor protein discovered in 1963, almost 20 years before kinesin—and among the largest proteins encoded in the genome. Dynein was less studied than kinesin because of its intractable size. In 2006, Vale’s lab figured out a way to express and purify the large protein from yeast and showed, using single-molecule assays, how the protein moves. His lab also studies T-cell signaling, using reconstitution systems, microscopy, and biochemistry. Additionally, his laboratory has made several contributions in RNA biology, mitosis and cell division, and microtubule-binding proteins.

Biology for the people. In 2006, Vale started iBiology, a collection of freely accessible online videos that feature leading biologists, who explain concepts and talk about their research. “The idea for the project came to me when I flew to India for the first time and gave a talk to 150 people in a country with a population of 1.3 billion. The way we communicate science in oral form is different from written communication. I wanted people all over the world to have the ability to hear leading scientists talk about their work, not just the small proportion within elite institutions.” Vale is increasingly devoting more time to the project and expanding its scope to include science education.

Science ambassador. Vale also started the Young Investigators’ Meeting (YIM) in 2009 to give junior scientists in India the opportunity to build a network and find mentors and resources. He started a website and organization called IndiaBioscience.org. “YIM is about the science, but also provides insights into career development and how to develop the skill set for running a laboratory, for which there are plenty of resources in the U.S. but fewer in India. The country is in an important transitional moment where its economy is growing and so is its scientific enterprise. India needs to invest time and resources into building a scientific culture and supporting young scientists,” he says.

Changing tides. In 2015, Vale founded ASAPbio, an organization that promotes the use of preprints to accelerate scientific publication. “I think it’s really had an impact because two years ago, biologists really did not know what preprints were. Now, the concept has taken off, and preprints have grown considerably and have caught the attention of funding agencies and scientists. It has been really gratifying to see the evolution of developing a more open culture of sharing scientific data. Preprints don’t replace traditional peer review, but they can work alongside publishing as a way to get results out there faster,” says Vale. “A big motivation for this effort is to help young scientists, because their papers can be stuck in review for a long time, and publications are the way scientists can demonstrate productivity. I am amazed how the preprint culture in biology is advancing. It shows that if you put an issue in front of the scientific community and engage the community in open discussion and debate, the culture in science can change in positive ways.”

Greatest Hits

With Michael Sheetz, Thomas Reese, and Bruce Schnapp, discovered that the bidirectional transport of organelles within axons occurs along microtubules

With Michael Sheetz and Thomas Reese, purified and identified a novel motor protein that he named kinesin, which moves cargo along microtubules and allows for transport within cells

Established that an individual kinesin molecule pulls itself and its load along a microtubule and that the kinesin motor protein is able to take many steps along the microtubule without detaching

Using Xenopus egg extract, discovered the first microtubule-severing factor

Developed the first single-molecule fluorescence motility assay for a motor protein

Founded iBiology.org, ASAPbio.org, and IndiaBioscience.org, as well as other public-service and educational efforts

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